It is known, from statistics published in 1995, that the number of diabetes patients in the United States is about 7.8 million, or about 3.4% of the total U.S. population. This number has been steadily rising over the past 25 years. Approximately 10%, or about 0.8 million such patients are insulin dependent (IDDM) patients. Further, of the remaining approximately 7 million non-insulin dependent diabetes mellitus (NIDDM) patients, about 30% use insulin. The percentage of NIDDM patients receiving insulin treatment increases with the duration of NIDDM from 25% (0-4 years) to 60% (greater than 20 years). From these statistics, it is seen that there is a substantial and an increasing need for a convenient and reliable system for eliminating the need of insulin injections for IDDM patients in particular, as well as for many NIDDM patients who receive insulin treatments.
One approach to providing insulin so as to eliminate the need of insulin injections is the transplant of encapsulated islets (Xeno, allo and auto type) of Langerhans. Research in the field of encapsulating islets by means of immunoisolative membranes has been extensively addressed, but a number of obstacles to this approach remain to be overcome. The technical aspects of the encapsulation process, i.e., how to improve the mechanical and chemical aspects of the capsules, are being addressed. See, for example, U.S. Pat. No. 5,190,041, which discloses capsules containing glucose-sensitive cells such as islets of pancreatic beta cells. Work is also progressing with respect to increasing survival times of such encapsulated islets, e.g., from months to years, or even a lifetime. However, other functional aspects of such capsules provide greater difficulties. Specifically, adequate restoration of normoglycaemia, as well as normal response to physiologic glucose stimulus, requires optimal glucose and insulin kinetics between the transplant and the blood stream. The most commonly used transplant sites, intra-portal as well as the intra-peritoneal cavity, present specific kinetic problems. Alternative transplantation sites in close contact to the blood stream do not permit sufficiently high volume transplants. Although the lack of physical volume might be offset by improving the effectiveness of the islets, functional limitations remain substantial. Further, the limited ability to respond to elevated blood glucose values with an appropriate insulin response remains a problem.
The overall object of this invention is to provide an improved insulin response to a diabetic patient, without need for insulin injection. The problem points to modifying or somehow changing the normal behavior of the transplant, or the patient's pancreas, so as to increase insulin production. Further, with respect to transplanted encapsulated islets, there is a need for improved kinetics since the transplant does not receive normal glucose signals. Although normoglycaemia can be reached with a transplant, an optimum physiological response to a glucose stimulus requires taking into account the blood glucose and insulin kinetics. For an intra-peritoneally transplanted islet graft, glucose kinetics is limited by diffusion from the blood stream towards the peritoneal fluid and towards the capsule, entrance to the membrane, spreading of the glucose over the islets by passive diffusion and the accomplishment of an insulin response by the islets. Insulin kinetics are determined by diffusion of insulin through the capsule membrane and the peritoneal fluid. Finally, the systemic blood vessel wall is reached and the insulin diffuses into the portal circulation, first passing the liver, and then entering the systemic circulation.
The primary mechanisms involved in the synthesis and exocytosis of insulin are largely known. At glucose concentrations below three mM, the beta cell is electrically silent with a resting membrane potential of about -70 mV. The resting potential is principally determined by the activity, (i.e., open-close probability state) of the ATP dependent outward potassium channels, i.e., the K-ATP channel. As a consequence of raising external glucose, as with food in-take, the ATP:ADP ratio increases, which leads to the closure of K-ATP channels, limiting outward flow of potassium, opening of voltage gated inward calcium (VGIC) channels and subsequent depolarization of the membrane. This mechanism implements the physiological glucose sensor. If the glucose level is greater than 4 mM, depolarization is sufficient to reach the threshold potential of about -40 mV, at which electrical activity is initiated. A subsequent rise in free cytosolic calcium triggers insulin secretion and activates calcium gated outward potassium channels, enhancing potassium efflux, which in turn inactivates VDDC, leading to cell repolarization. The electrical activity typically shows slow oscillations of depolarization (slow waves) with super imposed higher frequency burst activity during such depolarized burst episodes. During burst activity, spikes are seen with peak amplitudes of about 20 mV on a plateau of -30 mV. The firing frequency of a burst decreases gradually until repolarization.
It is known that beta cells can be activated by electrical field stimulation; further, beta cells in the pancreas can be activated by stimulation of the vagal nerve. As discussed further below, the burst length of a stimulated depolarization is substantially of equal length as a spontaneous depolarization. To achieve capture, i.e., to trigger the depolarization burst, the electrical stimulation pulse needs to exceed the membrane potential threshold, e.g., about -40 mV. From literature studies, it is known that a transmembrane current of 3 micro amperes is subthreshold, while a 4 microampere pulse achieves islet activation. Likewise, the burst activity can be terminated by a stimulus pulse which even further depolarizes the membrane, causing subsequent closure of voltage gated inward calcium channels, leading to premature repolarization. What has heretofore remained unknown is a capability of increasing insulin release from pancreatic beta cells (oxocytosis) by stimulation of the beta cells directly, or by nerve stimulation.